Patients with Alzheimer's disease (AD) develop deposits of abnormally aggregated amyloid -protein (A) in neuritic plaques and cerebral vessels in the brain. Accumulation of abnormally aggregated A is postulated to be the initiating event leading to neurodegeneration and dementia in AD. Therefore, therapeutic strategies that clear and/or prevent A accumulation are predicted to be effective against AD. Fibrillar A deposits in the AD brain are accompanied by activated microglia. Fibrillar A can activate microglia through Toll-like receptors (TLRs) including TLR4. TLRs are a class of pattern-recognition receptors in the innate immune system. One of the important roles of TLRs is to activate monocytes/microglia in response to pathogens and damaged host cells, and to clear pathogens, damaged tissues, and accumulated wastes. Activation of microglia through TLR4 markedly boosts ingestion and/or clearance of A. We have shown that AD model mice homozygous for a loss-of-function mutation of TLR4 had an increase in A load in the brain, compared to AD model mice with TLR4 wild-type alleles. In response to TLR4 ligands, TLR4 signals through the adaptor proteins, myeloid differentiation factor 88 (MyD88) and/or Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon- (TRIF), MyD88-dependent and MyD88-independent/TRIF-dependent pathways, respectively. In order to determine the role of the MyD88 pathways in A clearance, we have investigated the effects of MyD88 deficiency (MyD88-/-) on A accumulation in an AD mouse model. MyD88 deficiency decreased cerebral A load in an AD mouse model. Therefore, we hypothesize that the TLR4-mediated MyD88-dependent pathway exacerbates cerebral -amyloidosis in vivo and that TLR4-mediated MyD88-independent (TRIF-dependent) signaling pathways play a significant role in clearing A deposits from the brain. These hypotheses are investigated in Aim 1 and 2. All TLRs, with the exception of TLR3, activate the MyD88 pathways, whereas TLR3 and TLR4 activate the TRIF pathways. We further hypothesize that TLR3 agonists are effective in ameliorating cerebral A-amyloidosis in an AD mouse model. The latter hypothesis is tested in Aim 2. We will test if TLR4 activation by A is required for A clearance by TRIF signaling in Aim 2, also. The specific aims are (Aim 1) to treat MyD88-deficient (MyD88-/-) and MyD88-sufficient (MyD88+/+) AD mouse models with TLR4 ligand or PBS (vehicle) and compare cerebral A load and inflammation between the groups and (Aim 2) to treat TLR4 mutant and TLR4 wild-type AD mouse models with a TLR3 agonist or PBS and compare cerebral A load and inflammation between the groups. The long term goals of this research are to determine the roles of TLR signaling in AD progression and to establish the logical basis for developing safe and effective immunotherapy for AD.